Sedaka Randee, Huang Jifeng, Yamaguchi Shinobu, Hallit Emily, Moran-Reyna Aida, Hsu Jung-Shan, Lovelady Caleb, Fujihashi Ayaka, Sako Mohammad, Kasztan Malgorzata, Benavides Gloria, Wilson Landon, Darley-Usmar Victor, Barnes Stephen, Saigusa Takamitsu
Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Function (Oxf). 2025 Aug 1;6(4). doi: 10.1093/function/zqaf026.
Dietary load and composition are known contributors that accelerate cyst growth in polycystic kidney disease (PKD). High protein intake, which increases amino acid burden in the kidneys, is one such factor. Despite identical protein load, a plant-based wheat-gluten (WG) diet was recently reported to blunt the inflammatory response of animal-based casein diet in a hypertensive model. Considering the importance of pro-inflammatory signals on cystogenesis in PKD, we therefore sought to determine whether a WG compared to casein diet would decelerate cyst progression. Tamoxifen-inducible, global Pkd1 knockout mice were fed either a low casein (6%), high casein (60%), or high wheat-gluten (60%) protein diet for 6 wk. In a separate cohort, mice were gavaged daily with vehicle, lysine, or glutamine for 4 wk while maintained on a normal protein (18%) diet. Tissues were used for histology, flow cytometry, mitochondrial function, metabolomics, and various biochemical assays. WG-fed mice had better kidney function and reduced kidney macrophage percentages, proinflammatory cytokine expression, and cyst growth compared to casein-fed mice. Protein source did not alter kidney mitochondria function. Supplementation with lysine, the highest amino acid in casein versus WG diet, increased kidney cyst growth, acid production, and metabolic disarray. This did not occur with glutamine supplementation, the highest amino acid in WG versus casein diet, despite increased glomerular filtration rate with both amino acids. Neither supplementation mounted an inflammatory response. A plant-based, low-lysine diet slows disease burden in a murine model of PKD. This easily modifiable diet may be a beneficial intervention for PKD patients.
饮食负荷和组成是已知的加速多囊肾病（PKD）囊肿生长的因素。高蛋白摄入会增加肾脏中的氨基酸负担，就是这样一个因素。尽管蛋白质负荷相同，但最近有报道称，在高血压模型中，基于植物的小麦麸质（WG）饮食可减轻基于动物的酪蛋白饮食的炎症反应。鉴于促炎信号对PKD囊肿形成的重要性，因此我们试图确定与酪蛋白饮食相比，WG饮食是否会减缓囊肿进展。用他莫昔芬诱导的全身性Pkd1基因敲除小鼠分别喂食低酪蛋白（6%）、高酪蛋白（60%）或高小麦麸质（60%）的蛋白质饮食6周。在另一个队列中，小鼠在维持正常蛋白质（18%）饮食的同时，每天用赋形剂、赖氨酸或谷氨酰胺灌胃4周。组织用于组织学、流式细胞术、线粒体功能、代谢组学和各种生化分析。与喂食酪蛋白的小鼠相比，喂食WG的小鼠肾功能更好，肾脏巨噬细胞百分比、促炎细胞因子表达和囊肿生长减少。蛋白质来源未改变肾脏线粒体功能。补充酪蛋白中相对于WG饮食含量最高的氨基酸赖氨酸，会增加肾脏囊肿生长、酸产生和代谢紊乱。而补充WG中相对于酪蛋白饮食含量最高的氨基酸谷氨酰胺则不会出现这种情况，尽管两种氨基酸都会增加肾小球滤过率。两种补充剂均未引发炎症反应。基于植物的低赖氨酸饮食可减轻PKD小鼠模型中的疾病负担。这种易于调整的饮食可能对PKD患者是一种有益的干预措施。
